Mass production of functional human pancreatic β‐cells: why and how?

Scharfmann, Raphaël; Didiesheim, M.; Richards, Pamela Spence; Chandra, Vikash; Oshima, Masaya; Albagli, Olivier

doi:10.1111/dom.12728

Cited by 28 publications

(17 citation statements)

References 104 publications

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“…Our study reveals that Elovl2 is expressed in the pancreatic β cell lines MIN6 and Beta TC-tet and in the human β cell line EndoC-βH1 [51]. Correspondingly, recently published transcriptomic data [52], [53] also demonstrate detectable, although low, levels of Elovl2 mRNA in adult human β cells.…”

Section: Discussionsupporting

confidence: 75%

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

Cruciani-Guglielmacci

Bellini

Denom

et al. 2017

Molecular Metabolism

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ObjectiveIn type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress.MethodsMale mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis.ResultsA module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines.ConclusionOur results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.

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Section: Discussionsupporting

confidence: 75%

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

Cruciani-Guglielmacci

Bellini

Denom

et al. 2017

Molecular Metabolism

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“…More recently, yet, cellular responses of this cell line to cytokine toxicity were observed to be similar to primary human beta‐cells . As with 1.1B4 cells, EndoC‐beta cell lines have been exploited for research in multiple areas including beta‐cell physiology and survival and the pathogenesis of diabetes, as has been recently documented in an excellent review by the creators of these cell lines . Taken together, 1.1B4 and EndoC‐beta cells are well‐characterized clonal human pancreatic beta‐cell models and are useful tools to study human beta‐cell biology.…”

Section: Human Beta‐cell Line Development and Potential For Therapeutmentioning

confidence: 87%

Cellular models for beta‐cell function and diabetes gene therapy

2018

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Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

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“…Moreover, they contain b-cells in different proportions from one preparation to another, giving rise to data variability (25). The difficulty of generating functional human b-cell lines has also represented a major limitation for decades (26). The present work mainly focuses on glucose-regulated gene expression in pancreatic b-cells in a human context, using both human islets from donors and the recently developed functional human b-cell line EndoC-bH1 (17).…”

Section: Discussionmentioning

confidence: 99%

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

et al. 2017

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Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels.

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Mass production of functional human pancreatic β‐cells: why and how?

Cited by 28 publications

References 104 publications

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

Cellular models for beta‐cell function and diabetes gene therapy

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

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